Autoimmune disease in NZB/NZW F1 (B/W) mice can be arrested by sustained treatment with monoclonal antibodies (Mab) to L3T4, the mouse homologue for CD4 in humans. Based on this observation, we will test two hypotheses that are important to an understanding of the pathogenesis of autoimmunity and to the potential use of MAb to CD4 in humans. Hypothesis 1: Suppression of murine lupus with MAb to L3T4 reflects inhibition of T cell function and does not require profound depletion of L3T4+ cells. Suppression of autoimmunity by anti- L3T4 could be due either to depletion of target cells or to inhibition of their function. To resolve this issue, we will determine whether F(ab')2 fragments of anti-L3T4 can retard autoimmunity without depleting L3T4+ cells. We will also determine whether low doses of anti-L3T4, sufficient to reduce but not eradicate L3T4+ cells, can retard autoimmunity without causing severe or sustained suppression of normal immunity. Previous attempts to examine these approaches have been confounded by a host immune response to therapy. We will circumvent this problem by tolerizing mice with a single high- dose of MAb to L3T4. These studies will provide insight into the mechanism by which anti-L3T4 suppresses autoimmunity. They will also be relevant to the potential use of anti-CD4 in humans, by testing two rapidly reversible approaches to therapy that will minimize the risks caused by prolonged immune suppression, and by demonstrating a possible solution to the problem of host immunity to anti-CD4 MAb. Hypothesis 2: Early B cell maturation and late B cell malignancy in B/W mice is independent of T cell help. Several B cell abnormalities could contribute to autoimmunity in B/W mice. These include: spontaneous and mitogen-induced B cell hyperactivity; (ii) age-dependent switch from IgM to IgG production: (iii) increased Ly-1+B cells; and (iv) B cell malignancies. We will determine whether these B cell abnormalities are, like autoimmune disease, dependent on L3T4+ T cells or whether they occur independently. This will be accomplished by using MAb to deplete L3T4+ cells from B/W mice beginning early in life (in utero, if necessary). These studies will provide insight into the pathogenesis of murine lupus by helping to determine at what stage in pathogenesis L3T4+ T cells exert their influence. They will also clarify the role of specific B cell defects in the expression of autoimmune disease, and they will identify potentially pathologic B cell abnormalities that would not be affected by altering T cell regulation but rather would require alternative therapies.